DESCRIPTION: Recently a protein was cloned that has high homology with UCP-1 and was identified, UCP-2. Given this high homology with UCP-1 and its wide tissue distribution including the muscle, the applicant's goal is to ascertain the functional significance of the protein. He hypothesizes that UCP-2 is a mitochondrial uncoupling protein, and that it plays a significant role in thermogenesis and overall energy balance. To address this hypothesis the applicant proposes to: (1) determine the tissue, cellular and subcellular localization of UCP-2, and to assess the regulation of its expression by metabolic states, cytokines, and hormones; (2) determine the consequences of UCP-2 expression on mitochondrial and cellular respiration and to identify intracellular signals which regulate UCP-2 activity; (3) identify cis-regulatory elements and trans.-acting factors which are importent in controlling UCP-2 gene expression; and (4) determine in vivo the physiologic consequences of altered UCP-2 gene expression on systemic energy balance using transgenic mice and knock-our mice. In a followup letter, Dr. Lowell reports that his group (and others) have cloned another UCP, UCP-3. He now plans to focus most attention on UCP-3 rather than UCP-2, though in some experiments both can be studied.